The goal of this proposal is to determine the functional role of mouse FcRH3, a member of the newly identified Fc receptor homolog (FcRH) multigene family. Proteins encoded by these phylogenetically conserved genes have variable numbers of Ig domains of five different subtypes and possess conserved tyrosine-based activating and/or inhibitory signaling motifs in their cytoplasmic tails. Family members are differentially expressed among peripheral B lineage subpopulations and may be overexpressed by human B lineage malignancies;all features that strongly suggest their function is to modulate B cell effector responses. The long-term objective of our studies is to investigate the biological role of FcRH molecules in innate and adaptive immunity, and determine how their functions are subverted in autoimmunity and B lineage malignancies. FcRH3 is a B cell specific gene that is unique in its expression pattern. A panel of monoclonal antibodies identifies its expression distinctly among MZ and B1 B cells cytometrically and its topographical enrichment in the splenic MZ histologically. Consistent with its possession of ITIM and ITAM- like sequences, FcRH3 is tyrosine phosphorylated in B cells. Following co-ligation with the B cell receptor, however, FcRH3 signaling capacity appears to differ as a function of location and the cell type that expresses it. Furthermore, preliminary findings do not support its function as an Fc receptor. These results suggest that FcRH3 is a novel immunoregulatory marker of MZ and B1 B lineage cells. Our preliminary data have led to the hypothesis that FcRH3 is an important regulator of MZ and B1 B cell development and effector function. This will be tested in three Specific Aims: 1) to determine the signaling potential of FcRH3 tyrosine-based motifs;2) to examine the functional consequences of FcRH3 deficiency in mice;and 3) to characterize the FcRH3 ligand(s). The studies proposed here will clarify the functional role of one representative family member as a model for determining the biologic capacity of the Fc receptor homolog family in immunity. The shared structural features and expression patterns for representative FcRH family members in humans and mice indicate conserved biological function and support the idea that full understanding of murine family members will yield insight into the function of their human counterparts.